Neonatal medicine

Neonatal medicine
The article should have been published within the past 5 years in a peer-reviewed professional journal. (The features of a peer-reviewed journal are listed below). Library and research resources are provided in the Course Menu. Review the attached handouts before you begin the process:

1) How to Review a Journal Article,
2) Sample Format for Reviewing Journal Articles and
3) the Journal Article Review rubric, which will be used for grading.
Note that a Journal Article Review is not a summary of the article, but includes the following components: An abstract

1. What is the purpose of this article? (this section includes a brief summary of the article)
2. Why is it important to investigate or examine the subject of the article?
3. How are the authors carrying out the task? Are their methods and comments appropriate and adequate to the task?
4. What do they claim to have found out? Are the findings clearly stated?
How to Review a Journal Article:
Suggestions for First-Time Reviewers and Reminders for Seasoned Experts
Guidelines for Reviewing
Here are some things you should consider as you examine a manuscript and write your
review:
Look for the “intellectual plot-line” of the article. You can do this from first skimming
through the manuscript and then giving it a once-over read. As you do this, ask the major
questions that are central to the review process:
1. What is the purpose of this article?
2. Why is it important to investigate or examine the subject of the article?
3. How are the authors carrying out the task? Are their methods and comments
appropriate and adequate to the task?
4. What do they claim to have found out? Are the findings clearly stated?
5. How does this advance knowledge in the field?
How well do the authors place their findings or comments within the context of ongoing
scholarly inquiry about this topic? Look at the organization of the article. Can you find
answers to the above questions quickly and easily? Can you trace the logic consistently
from the opening paragraphs to the conclusion?
Then go back to the opening paragraphs of the article. Is the groundwork adequately and
clearly laid to guide readers into the topic that is being addressed? Is it clear what the
authors are talking about? Do they make the case that this is an important area for inquiry
or examination?
An early section of many articles is usually a review of the existing literature on this topic.
Do the authors present a convincing line of argument here—or does it appear that they
are just name-dropping (citing sources that may be important, without a clear underlying
logic for how they may be important)? Do the authors focus on ideas, or merely on
discrete facts or findings? Have they given sufficient attention to theory—the cumulative
attempts at prior explanations for the questions they are investigating? In short: How well
do the authors set the stage for the problem or issue that they are reporting?
In the case of a research article, the section presenting research results is surely the heart
of the article—though not its soul (which the reader should find in the opening
paragraphs and in the discussion section). Reviewers might consider four questions here:
1. Does the results section tell a story—taking the reader from the research questions
posed earlier to their answers in the data? Is the logic clear?
2. Are the tables and figures clear and succinct? Can they be “read” easily for major
findings by themselves, or should there be additional information provided? Are
the authors’ tables consistent with the format of currently accepted norms
regarding data presentation? Are the tables and/or figures necessary?
3. Do the authors present too many tables or figures in the form of undigested
findings? Are all of them necessary in order to tell the story of this research
2
inquiry; or can some be combined? Remember that tables and figures are very
expensive and can take up a lot of space. Also remember that undigested data
obscure rather than advance the cumulative development of knowledge in a field.
4. Are the results presented both statistically and substantively meaningful? Have the
authors stayed within the bounds of the results their data will support?
The writing style is important. Consider the three guidelines for successful
communication—to be clear, concise, and correct — and whether the authors have
achieved it:
1. Is the writing clear? Do the authors communicate their ideas using direct,
straightforward, and unambiguous words and phrases? Have they avoided jargon
(statistical or conceptual) that would interfere with the communication of their
procedures or ideas? Have they clearly and satisfactorily explained the key
concepts relevant to the article?
2. Is the writing concise? Are too many words or paragraphs or sections used to
present what could be communicated more simply?
3. Is the writing correct? Many writers have only a rudimentary grasp of grammar
and punctuation, and that results in meandering commas, clauses in complex
sentences that are struggling to find their verbs, and adjectives or even nouns that
remain quite ambiguous about their antecedents in the sentence. Does the article
have a foreign accent, i.e., is it clear that a native speaker of English did not write
it? These are not merely technical issues of grammar to be somehow dealt with by
a copy-editor down the line. Rather they involve the successful communication of
a set of ideas to an audience; and this is the basis of scholarship today.
Your evaluation to the editor: Should this paper be (a) rejected for this journal? or (b)
does it show sufficient promise for revision, in ways that you have clearly demonstrated in
your review, to encourage the authors to invest significant time and energy in revision for
this journal? Your bottom-line advice to the editor is crucial. Make a decision; state it
clearly in your remarks to the editor in the space provided. Remember that not all of the
articles submitted to a journal will be published.
Some reasons to reject a manuscript:
1. The issues have already been addressed in prior studies;
2. The data have been collected in such a way as to preclude useful investigation;
3. The manuscript is not ready for publication—it is incomplete, in the improper
format, or error-ridden.
Most rejected articles do find a home in other journals. Don’t tease authors with hopes for
publication in the NECTFL Review if you feel it is not likely.
Good Reviews and Bad Reviews
A good review is supportive, constructive, thoughtful, and fair. It identifies both strengths
and weaknesses, and offers concrete suggestions for improvements. It acknowledges the
reviewer’s biases where appropriate, and justifies the reviewer’s conclusions.
3
A bad review is superficial, nasty, petty, self-serving, or arrogant. It indulges the reviewer’s
biases with no justification. It focuses exclusively on weaknesses and offers no specific
suggestions for improvement.
Adapted from “Information from Reviewers” of Foreign Language Annals, a publication of the American
Council on the Teaching of Foreign Languages (ACTFL). Retrieved from http://www.actfl.org/i4a/pages/
index.cfm?pageid=5163 on October 25, 2010. Used by permission.
original article
T h e new engl and journa l o f medicine
n engl j med 363;24 nejm.2320 org december 9, 2010
Neonatal Abstinence Syndrome after
Methadone or Buprenorphine Exposure
Hendrée E. Jones, Ph.D., Karol Kaltenbach, Ph.D., Sarah H. Heil, Ph.D.,
Susan M. Stine, M.D., Ph.D., Mara G. Coyle, M.D., Amelia M. Arria, Ph.D.,
Kevin E. O’Grady, Ph.D., Peter Selby, M.B., B.S., Peter R. Martin, M.D.,
and Gabriele Fischer, M.D.
From the Departments of Psychiatry and
Behavioral Sciences and Obstetrics and
Gynecology, Johns Hopkins University
School of Medicine, Baltimore (H.E.J.); the
Departments of Pediatrics, Psychiatry, and
Human Behavior, Jefferson Medical College,
Thomas Jefferson University, Philadelphia
(K.K.); the Departments of Psychiatry
and Psychology, University of
Vermont, Burlington (S.H.H.); the Department
of Psychiatry and Behavioral
Neurosciences, Wayne State University
School of Medicine, Detroit (S.M.S.); the
Department of Pediatrics, Warren Alpert
Medical School of Brown University, Providence,
RI (M.G.C.); the Center for Young
Adult Health and Development (A.M.A.)
and Department of Psychology (K.E.O.),
University of Maryland, College Park; the
Departments of Family and Community
Medicine and Psychiatry, University of
Toronto, Toronto (P.S.); the Departments
of Psychiatry and Pharmacology and Addiction
Center, Vanderbilt University School
of Medicine, Nashville (P.R.M.); and the
Department of Psychiatry and Psychotherapy,
Addiction Clinic, Medical University
Vienna, Vienna (G.F.). Address reprint
requests to Dr. Jones at the Center for
Addiction and Pregnancy, D-3 E., Johns
Hopkins Bayview Medical Center, 4940
Eastern Ave., Baltimore, MD 21224, or at
hjones18@jhmi.edu.
N Engl J Med 2010;363:2320-31.
Copyright © 2010 Massachusetts Medical Society.
ABSTR ACT
BACKGROUND
Methadone, a full mu-opioid agonist, is the recommended treatment for opioid
dependence during pregnancy. However, prenatal exposure to methadone is associated
with a neonatal abstinence syndrome (NAS) characterized by central nervous
system hyperirritability and autonomic nervous system dysfunction, which often requires
medication and extended hospitalization. Buprenorphine, a partial mu-opioid
agonist, is an alternative treatment for opioid dependence but has not been extensively
studied in pregnancy.
METHODS
We conducted a double-blind, double-dummy, flexible-dosing, randomized, controlled
study in which buprenorphine and methadone were compared for use in the comprehensive
care of 175 pregnant women with opioid dependency at eight international
sites. Primary outcomes were the number of neonates requiring treatment for
NAS, the peak NAS score, the total amount of morphine needed to treat NAS, the
length of the hospital stay for neonates, and neonatal head circumference.
RESULTS
Treatment was discontinued by 16 of the 89 women in the methadone group (18%)
and 28 of the 86 women in the buprenorphine group (33%). A comparison of the
131 neonates whose mothers were followed to the end of pregnancy according to
treatment group (with 58 exposed to buprenorphine and 73 exposed to methadone)
showed that the former group required significantly less morphine (mean dose, 1.1 mg
vs. 10.4 mg; P<0.0091), had a significantly shorter hospital stay (10.0 days vs. 17.5 days,
P<0.0091), and had a significantly shorter duration of treatment for the neonatal
abstinence syndrome (4.1 days vs. 9.9 days, P<0.003125) (P values calculated in accordance
with prespecified thresholds for significance). There were no significant
differences between groups in other primary or secondary outcomes or in the rates
of maternal or neonatal adverse events.
CONCLUSIONS
These results are consistent with the use of buprenorphine as an acceptable treatment
for opioid dependence in pregnant women. (Funded by the National Institute
on Drug Abuse; ClinicalTrials.gov number, NCT00271219.)
The New England Journal of Medicine
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Copyright © 2010 Massachusetts Medical Society. All rights reserved.
Methadone, Buprenorphine, and Neonatal Abstinence Syndrome
n engl j med 363;24 nejm.org december 9, 2010 2321
Opioid dependence during pregnancy
is compounded by multiple risk factors
contributing to adverse maternal, neonatal,
and long-term developmental consequences.
1-6 Improved treatment options should reduce
the public health and medical costs associated
with the treatment of neonates exposed to opioids,
which in 2009 was estimated at $70.6 million to
$112.6 million in the United States alone.7 Just as
the use of methadone in nonpregnant patients
with opioid dependence improves patient outcomes,
8 its use as part of a comprehensive approach
to the care of pregnant women improves
maternal and neonatal outcomes, as compared
with no treatment and with medication-assisted
withdrawal.4,9,10 However, exposure to methadone
in utero can result in a neonatal abstinence syndrome
(NAS) characterized by hyperirritability of
the central nervous system and dysfunction in the
autonomic nervous system, gastrointestinal tract,
and respiratory system.11 When left untreated,
NAS can result in serious illness (e.g., diarrhea,
feeding difficulties, weight loss, and seizures)
and death.11 Methadone-associated NAS often requires
prolonged hospitalization, pharmacologic
intervention, and monitoring.
Buprenorphine, a partial mu-opioid agonist
and kappa-opioid antagonist, effectively treats
opioid dependence.12 Its low intrinsic receptor
efficacy results in a less-than-maximal opioid
effect13 and a diminished risk of overdose, as compared
with methadone. In nonpregnant adults,
the effects of abrupt withdrawal of buprenorphine
are minimal relative to the effects of
withdrawal of full mu-opioid agonists.14,15 Buprenorphine’s
pharmacologic advantages led to
prospective open-label and controlled studies of
its use in prenatal treatment,16-19 and the results
of some of these studies suggested that neonates
exposed to buprenorphine might be less likely to
require treatment for NAS than those exposed to
methadone.20 Recent studies of methadone and
buprenorphine have had inconsistent results with
respect to NAS outcomes.21-26 Given the calls to
increase representation of pregnant women in
medication research,27 we conducted the Maternal
Opioid Treatment: Human Experimental Research
(MOTHER) project, a multicenter, randomized,
controlled trial comparing buprenorphine with
methadone for the treatment of opioid-dependent
pregnant patients.28
Methods
Study Sites and Participants
Between May 4, 2005, and October 31, 2008,
opioid-dependent women between the ages of 18
and 41 years with a singleton pregnancy between
6 and 30 weeks of gestation (calculated on the
basis of the last menstrual period and confirmed
by ultrasonographic results) were screened and
recruited at eight international sites — six in the
United States and one each in Austria and Canada.
Seven sites contributed randomized data; one
site screened participants but did not complete
randomization.
Women were eligible for participation in the
study if they had no medical or other conditions
contraindicating participation, were not subject
to pending legal action that might prevent their
participation, had no disorders related to the use
of benzodiazepines or alcohol, and did not plan
to give birth outside the hospital at the study site
(Fig. 1). Study referral sources included community
providers, self-referral, and the site’s treatment
program.28-30
Screening for eligibility consisted of a comprehensive
battery of tests (see Fig. 1 in the Supplementary
Appendix, available with the full text of
this article at NEJM.org). The screening tests
were performed either at the time of treatment
initiation (in the case of patients who were new
to treatment) or after a patient’s request for a
change in her established treatment (e.g., in the
case of patients who were already being treated
with a mu-opioid agonist and who agreed to
randomization). Patients who were not eligible
for participation in the study were so informed
and transferred to standard care available at the
site’s clinic or at a local community clinic.
Each site’s local institutional review board approved
the study. All participants provided written
informed consent at the time of screening.
Buprenorphine tablets and the associated placebo
were supplied by Reckitt Benckiser Healthcare,
Hull, United Kingdom. These tablets were
distributed to U.S. study investigators by the National
Institute on Drug Abuse. Schering-Plough
distributed buprenorphine tablets and placebo to
Austrian investigators. Neither Reckitt Benckiser
Healthcare nor Schering-Plough had involvement
in the study design; data collection, analysis, or
interpretation; or manuscript preparation.
The New England Journal of Medicine
Downloaded from nejm.org on July 1, 2014. For personal use only. No other uses without permission.
Copyright © 2010 Massachusetts Medical Society. All rights reserved.
T h e new engl and journa l o f medicine
n engl j med 363;24 nejm.2322 org december 9, 2010
Study Medications and Patient Care
Before randomization, all participants received
rapid-release morphine sulfate as inpatients to
achieve medical stabilization and to ease the transition
to the double-blind medication.26,29,31 Qualifying
participants underwent randomization and
started the assigned study medication as inpatients.
A blinded, individualized dosing schedule was
used for the study medications, and a doubleblind
method was used to implement dose-unit
increases or decreases (with dose adjustments
of 2 mg for buprenorphine and 5 or 10 mg for
methadone). Dose adjustments entailed clinical
decisions based on medication adherence, the
participant’s request, urine toxicologic results,
and self-reported symptoms of withdrawal or
craving.26 Tablets of buprenorphine (Subutex,
Reckitt Benckiser) were used to avoid prenatal
exposure to naloxone. (Neither buprenorphine
175 Underwent randomization
1074 Patients were screened for eligibility
243 Did not provide consent
656 Were excluded
557 Failed to meet inclusion criteria
149 Had estimated gestational age outside
range
124 Were taking a benzodiazepine
105 Had medical reason
57 Were using alcohol
42 Had impending legal issue
19 Did not provide consent
17 Had psychological or psychiatric reason
12 Had multiple-fetus pregnancy
11 Were outside age range
10 Were undergoing detoxification
9 Were not opioid-dependent
2 Did not speak English or German
99 Were excluded for other reasons
86 Were assigned to receive
buprenorphine
89 Were assigned to receive
methadone
28 Discontinued study
26 Had voluntary reasons
20 Were dissatisfied with
medication
5 Missed 5 consecutive
dosing days
1 Withdrew
2 Had involuntary reasons
2 Were discharged for
administrative reason
16 Discontinued study
10 Had voluntary reasons
2 Were dissatisfied with
medication
4 Missed 5 consecutive
dosing days
2 Withdrew
2 Had other reason
6 Had involuntary reasons
2 Were discharged for
administrative reason
2 Lost pregnancy
1 Had medical issues
1 Was incarcerated
58 Completed the study 73 Completed the study
Figure 1. Screening, Randomization, and Rate of Treatment Completion, According to Study Group.
The New England Journal of Medicine
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Copyright © 2010 Massachusetts Medical Society. All rights reserved.
Methadone, Buprenorphine, and Neonatal Abstinence Syndrome
n engl j med 363;24 nejm.org december 9, 2010 2323
nor naloxone has been approved by the Food and
Drug Administration or the European Medicines
Agency for use during pregnancy.) A flexible
dose range of 2 to 32 mg of buprenorphine in
sublingual tablets was estimated to be equivalent
to 20 to 140 mg of methadone on the basis of
previously published data from clinical trials.32-34
Participants were required to receive daily
medications under observation in the study clinic.
They always received seven tablets (three in
the size of an 8-mg tablet and four in the size of
a 2-mg tablet) to place under the tongue for 5 minutes,
or until the tablets dissolved. Each tablet
contained buprenorphine or placebo. After receiving
these tablets, participants received liquid
containing methadone or placebo. Oral methadone
and flavor-masking concentrates were diluted
to provide the dose in a fixed volume (e.g.,
40 ml at U.S. sites and 50 ml in Vienna). Methadone
placebo was given in the same fixed volume
and included the same flavor-masking concentrates
as the active drug concentrate. All medications
were dispensed through regulated hospital
pharmacies or methadone clinics.
The study sites provided participants with
comprehensive care. To promote drug abstinence,
patients were given monetary vouchers in exchange
for providing urine samples that were
negative for opioids (other than buprenorphine
and methadone), other illicit drugs, and misuse
of prescription medications.26 On completion of
the study, participants could receive locally available
treatment.
Evaluation for NAS
NAS assessment was performed for a minimum
period of 10 days after birth. Hospitalized neonates
were examined every 4 hours by trained
staff. Neonates discharged from the hospital before
postnatal day 10 were expected to reside
with the mother in a residential setting, where
the evaluation was continued. NAS scores were
obtained twice daily, at least 8 hours apart, with
the use of a modified Finnegan scale (called the
MOTHER NAS scale), which includes 28 items11;
19 items were used for scoring and medication
decisions. Scores on the modified scale range
from 0 to 42, with higher scores indicating
more severe withdrawal. Original NAS-item definitions,
35 as well as the morphine medication
protocol,26,36 were refined before data collection
(Fig. 2 in the Supplementary Appendix);
the study was conducted in accordance with the
protocol.
An expert rater trained a highly experienced
rater at each site; by the end of training, the site
raters were required to obtain scores that were
within 2 points of the expert rater’s scores. To
maintain consistency in the reliability of the ratings
at each site, every 6 months the expert rater
provided a video of an infant undergoing NAS
assessment. An intraclass correlation coefficient
(ICC[2,2]) for the degree of agreement37 between
the expert rater and the site rater was estimated;
the lowest coefficient exceeded 0.94, indicating
excellent agreement between the raters.
Study Outcomes and Adverse Events
The five primary neonatal outcome measures
were the number of neonates requiring treatment
for NAS, peak NAS score, total amount of morphine
needed for treatment of NAS, length of
hospital stay, and head circumference. The seven
secondary neonatal outcomes were the number
of days during which medication was given for
NAS, weight and length at birth, preterm birth
(defined as birth at <37 weeks of gestation), gestational
age at delivery, and 1-minute and 5-minute
Apgar scores. The nine secondary maternal outcomes
were cesarean section, weight gain, abnormal
fetal presentation during delivery, anesthesia
during delivery, the results of drug screening at
delivery, medical complications at delivery, study
discontinuation, amount of voucher money earned
for drug-negative tests, and number of prenatal obstetrical
visits. Adverse events for all participants
were categorized on the basis of the Medical Dictionary
for Regulatory Activities (version 10.0) system of
organ classes and predefined categories of events.
Statistical Analysis
Bonferroni’s principle was used to set the familywise
alpha level at 0.01 (nominal alpha level,
0.05 ÷ 5) for each of the five primary outcome
measures at the time of the initial study design;
an interim analysis requested by the data safety
and monitoring board resulted in a recalculation
of the alpha level on the basis of the O’Brien–
Fleming spending function, such that the end-oftrial
alpha level was 0.0091 for each primary outcome
measure. Bonferroni’s principle was also
used to set the family-wise alpha level at 0.003125
(nominal alpha level, 0.05 ÷ 16) for the secondary
outcome measures.
The New England Journal of Medicine
Downloaded from nejm.org on July 1, 2014. For personal use only. No other uses without permission.
Copyright © 2010 Massachusetts Medical Society. All rights reserved.
T h e new engl and journa l o f medicine
n engl j med 363;24 nejm.2324 org december 9, 2010
There were two fixed-effect factors in all analyses:
medication (buprenorphine vs. methadone)
and site (U.S. urban [Baltimore; Philadelphia; Detroit;
Providence, RI] vs. U.S. rural [Burlington,
VT; Nashville] vs. European [Vienna]). Pooling the
sites minimized the possibility that site heterogeneity
would adversely effect the analyses.30 Poisson
regression analyses were conducted for the
total amount of morphine needed to treat NAS,
neonatal length of stay in the hospital, number
of days of treatment for NAS, estimated gestational
age at delivery, amount of money earned
for drug-negative tests, number of prenatal obstetrical
visits, and Apgar scores at 1 minute and
5 minutes. Ordinary least-squares regression
analyses
were conducted for the peak score on the
NAS scale during the assessment period, infant
head circumference, and infant weight and length
at birth. Logistic-regression analyses were conducted
for the remaining dichotomous variables.
For medication effects, model-derived leastsquares
means are reported for normally distributed
outcome variables, model-derived exponentiated
estimated means for Poisson-distributed
outcome variables, and odds ratios for the logistic
regressions. To minimize the possibility that
the effects attributed to the assigned medication
might be due to differences in participant characteristics,
the analyses were repeated with the
inclusion of covariates selected on the basis of
their potential associations with the outcome
variables. (For details on covariates, see Table 1
in the Supplementary Appendix.)
Results
Characteristics of the Study Participants
A total of 16 of the 89 women in the methadone
group (18%) and 28 of the 86 women in the buprenorphine
group (33%) discontinued treatment
before delivery (P = 0.02 with an alpha level of
0.003125 for other secondary maternal outcome
measures). The baseline characteristics of participants
in the two medication groups, including
those who did not complete the study, are
shown in Table 1. There were no significant
Table 1. Baseline Characteristics of Women in the Methadone and Buprenorphine Groups, According to Whether They Completed
Treatment.*
Characteristic Completed Treatment Did Not Complete Treatment
Methadone
(N = 73)
Buprenorphine
(N = 58) P Value
Methadone
(N = 16)
Buprenorphine
(N = 28) P Value
Age (yr) 27.7±0.7 25.3±0.7 0.014 29.7±1.6 29.1±1.7 0.75
Race (%)† 0.26 0.26
White 85 91 69 71
Black 14 3 31 29
Other 1 5
Estimated gestational age of fetus (wk) 18.7±0.8 18.7±0.7 0.94 16.4±1.7 19.7±1.3 0.13
Education (yr) 11.3±0.3 11.3±0.2 0.91 11.6±0.4 11.3±0.3 0.47
Employed (%) 14 19 0.41 6 4 0.47
Legal status, criminally unencumbered (%) 80 88 0.20 69 71 0.26
Married (%) 15 9 0.26 13 18 0.31
Treatment during the previous 30 days (%)‡
Maintenance therapy with methadone
or buprenorphine
47 41 0.56 50 35 0.16
Detoxification 4 5 0.76 0 4 0.64
Neither maintenance therapy nor detoxification 52 54 0.80 47 70 0.17
Current cigarette smoker (%) 99 95 0.21 88 89 0.36
Composite score on Addiction Severity Index§
Drugs 0.30±0.01 0.28±0.01 0.16 0.29±0.03 0.34±0.02 0.15
Alcohol 0±0.01 0.01±0.01 0.40 0±0.01 0.02±0.01 0.11
The New England Journal of Medicine
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Copyright © 2010 Massachusetts Medical Society. All rights reserved.
Methadone, Buprenorphine, and Neonatal Abstinence Syndrome
n engl j med 363;24 nejm.org december 9, 2010 2325
between-group differences in these characteristics,
including measures of substance use. Among
the women who did not complete treatment, the
mean (±SD) number of days in the study was
35.1±35.2 (range, 4 to 155) for those in the methadone
group and 8.6±17.2 (range, 0 to 80) for
those in the buprenorphine group; 8 participants
in the buprenorphine group left the study on the
first day. “Dissatisfaction” with the study medication
was reported as the reason for discontinuation
by 71% of participants in the buprenorphine
group, as compared with only 13% of those in
the methadone group (Fig. 1). The mean doses of
methadone and buprenorphine at the time the
participants left the study were 87.3±21.8 mg
(range, 41.3 to 133.2) and 14.3±5.9 mg (range, 3.0
to 30.0), respectively.
Among the 131 participants who completed
the study (i.e., gave birth while receiving doubleblind
study medication), there were no significant
differences between the buprenorphine and
methadone groups with respect to any of the
baseline characteristics, including substance-use
measures (P>0.01 for all comparisons, with an
alpha level of 0.00227) (Table 1). Analyses of neonatal
outcomes are based only on this sample of
participants.
Primary Outcomes
The percentage of neonates requiring NAS treatment
did not differ significantly between groups
(P = 0.26), nor did the groups differ significantly
with respect to the peak NAS score (P = 0.04) or
head circumference (P = 0.04). There were signif-
Table 1. (Continued.)
Characteristic Completed Treatment Did Not Complete Treatment
Methadone
(N = 73)
Buprenorphine
(N = 58) P Value
Methadone
(N = 16)
Buprenorphine
(N = 28) P Value
Substance use
Cumulative lifetime (mo)
Heroin 45.7±5.4 25.4±6.0 0.01 60.2±13.5 50.7±10.4 0.58
Cocaine 34.1±5.9 22.5±6.6 0.19 40.6±13.6 39.3±10.5 0.94
Any alcohol 23.5±4.3 13.4±4.8 0.13 26.6±11.5 17.6±8.8 0.54
Benzodiazepines 7.2±2.2 7.9±2.5 0.83 10.4±3.4 6.6±2.6 0.38
Previous 30 days (days)
Heroin 8.7±1.5 8.7±1.7 0.99 11.6±3.4 16.6±2.6 0.25
Cocaine 3.9±1.0 3.6±1.1 0.85 8.1±2.9 7.6±2.3 0.93
Any alcohol 0.3±0.1 0.2±0.2 0.40 0.3±0.5 1.1±0.4 0.23
Benzodiazepines 0.8±0.3 0.9±0.3 0.86 0.1±0.5 0.8±0.4 0.23
Score for extent to which patient was troubled or bothered
by drug problems in previous 30 days¶
2.8±0.2 2.5±0.2 0.20 2.6±0.4 2.7±0.3 0.74
* Plus–minus values are means ±SE. Bonferroni’s principle was used to set the family-wise alpha level at 0.00227 for the between-group comparisons
(nominal alpha level, 0.05 ÷ 22 for the number of variables for which inferential tests were conducted); there were no significant
medication-group differences in either the sample of participants who completed the study or the sample that did not complete the study.
† Race was self-reported. The chi-square goodness-of-fit statistic is reported for a dichotomized variable of white race versus nonwhite race.
‡ Percentages for current treatment do not sum to 100 because the first two categories are not mutually exclusive and because of missing data.
In the methadone group that completed treatment, the number of patients with missing data was 2 for maintenance therapy with methadone
or buprenorphine and for neither maintenance therapy nor detoxification, whereas in the buprenorphine group that completed treatment, the
number of patients with missing data was 1 for detoxification and for neither maintenance therapy nor detoxification. In the methadone group
that did not complete treatment, the number of patients with missing data was 1 for detoxification and for neither maintenance therapy nor detoxification,
whereas in the buprenorphine group that did not complete treatment, the number of patients with missing data was 1 for maintenance
therapy with methadone or buprenorphine and detoxification, 2 for neither maintenance therapy nor detoxification, and 1 for both composite
scores on the Addiction Severity Index and for all items on substance use. Patients whose current treatment was characterized as maintenance
included those who elected induction and stabilization with an opioid agonist when entering treatment (one or more days before study
screening) or who were already receiving maintenance treatment at the time of study screening.
§ Composite scores for the Addiction Severity Index range between 0 and 1, with higher scores indicating a more severe problem.
¶ The question regarding the extent to which a patient was troubled or bothered by drug problems was answered on a 5-point Likert-type
scale, with 0 indicating “not at all” and 4 indicating “extremely.”
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icant differences between groups for the other
two primary outcome measures: the total amount
of morphine needed for the treatment of NAS
and the length of the hospital stay for neonates
(Table 2 and Fig. 2, and Table 1 in the Supplementary
Appendix). On average, neonates exposed to
buprenorphine required 89% less morphine than
did neonates exposed to methadone (mean total
doses of 1.1 mg and 10.4 mg, respectively;
P<0.0091 in accordance with prespecified thresholds
for significance), and spent, on average, 43%
less time in the hospital (10.0 vs. 17.5 days, respectively;
P<0.0091). Both these outcome measures
also differed significantly between the treat-
Table 2. Primary and Secondary Outcomes in the Methadone and Buprenorphine Groups.*
Outcome
Methadone
(N = 73)
Buprenorphine
(N = 58)
Odds Ratio
(95% CI) P Value
Primary outcomes
Treated for NAS — no. (%) 41 (57) 27 (47) 0.7 (0.2–1.8) 0.26
NAS peak score 12.8±0.6 11.0±0.6 0.04
Total amount of morphine for NAS — mg 10.4±2.6 1.1±0.7 <0.0091†
Duration of infant’s hospital stay — days 17.5±1.5 10.0±1.2 <0.0091†
Infant’s head circumference — cm 33.0±0.3 33.8±0.3 0.03
Secondary neonatal outcomes
Duration of treatment for NAS — days 9.9±1.6 4.1±1.0 <0.003125†
Weight at birth — g 2878.5±66.3 3093.7±72.6 0.03
Length at birth — cm 47.8±0.5 49.8±0.5 0.005
Preterm, <37 wk — no. (%) 14 (19) 4 (7) 0.3 (0.1–2.0) 0.07
Gestational age at delivery — wk 37.9±0.3 39.1±0.3 0.007
Apgar score
1 min 8.0±0.2 8.1±0.2 0.87
5 min 9.0±0.1 9.0±0.1 0.69
Secondary maternal outcomes
Cesarean section — no. (%) 27 (37) 17 (29) 0.6 (0.2–2.0) 0.23
Maternal weight gain — kg 8.6±1.0 8.3±0.9 0.80
Abnormal fetal presentation during delivery
— no. (%)
10 (14) 3 (5) 0.3 (0.0–2.4) 0.09
Analgesia during delivery — no. (%) 60 (82) 49 (85) 1.1 (0.3–4.8) 0.85
Positive drug screen at delivery — no. (%) 11 (15) 5 (9) 0.5 (0.1–2.7) 0.27
Medical complications at delivery — no. (%) 37 (51) 18 (31) 0.5 (0.2–0.9) 0.03
Did not complete study — no. (%) 16 (18) 28 (33) 2.6 (1.3–5.6) 0.02
Amount of voucher money earned for drugnegative
tests — U.S. $
1,570.00±121.72 1,391.39±123.59 0.31
No. of prenatal obstetrical visits 8.8±0.5 8.7±0.4 0.86
* Plus–minus values are means ±SE. In accordance with the alpha level chosen for the tests of significance, 99.09% confidence
intervals (CIs) were used for the primary outcome measures, and 99.6825% CIs were used for the neonatal and
maternal
secondary outcome measures. The number of patients who underwent randomization was 175, the number who
did not complete the study was 44, and the number who did complete the study was 131. A small percentage of data
was missing. For four of the five primary outcomes, the number of patients with missing data was 1 in each medication
group except for the outcome on length of hospital stay for neonates, for which no data were missing. For two of the
seven secondary neonatal outcomes, the number of patients with missing data was 1 in each medication group for days
treated for NAS and 1 in the methadone group for infant length at birth. For four of the nine secondary maternal outcomes,
the number of patients with missing data in the methadone group was 2 for maternal weight gain, 2 for abnormal
fetal presentation during delivery, 1 for positive drug screen at delivery, and 3 for amount of voucher money earned;
the number of patients with missing data in the buprenorphine group was 4 for maternal weight gain, 1 for positive drug
screen at delivery, and 1 for voucher money earned.
† These P values were calculated in accordance with prespecified thresholds for significance.
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Methadone, Buprenorphine, and Neonatal Abstinence Syndrome
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ment groups when the analyses were adjusted for
selected covariates (Table 1 in the Supplementary
Appendix).
Secondary Outcomes
One of the seven neonatal secondary outcome
measures differed significantly between groups:
neonates exposed to buprenorphine spent, on average,
58% less time in the hospital receiving
medication for NAS than did those exposed to
methadone (4.1 days vs. 9.9 days, P<0.003125 in
accordance with prespecified thresholds for significance).
This difference remained significant
in analyses adjusted for selected covariates (Table
1 in the Supplementary Appendix). There were
no significant between-group differences in any
of the nine maternal secondary outcomes (Table
2, and Table 1 in the Supplementary Appendix).
Subgroup Analyses
To address the possibility that differences in neonatal
outcomes between the two groups might
be explained by higher average levels of opioid
dependence in women who completed methadone
treatment than in those who completed buprenorphine
treatment, we performed post hoc
analyses that excluded the 25 participants whose
methadone dose at delivery exceeded 100 mg.
The between-group differences in the amount of
morphine required for the treatment of NAS and
the length of the hospital stay remained significant
(P<0.001 and P = 0.003, respectively). The
difference in the secondary outcome of duration
of hospitalization while infants were receiving
medication was no longer significant (P = 0.01).
Adverse Events
Assuming an alpha level of 0.05 (to maximize the
detection of differences between medications
with respect to adverse events), the methadone
group had higher rates of nonserious maternal
events overall (P = 0.003) and of nonserious maternal
cardiovascular events in particular (P = 0.01).
The two medication groups did not differ significantly
with respect to any serious maternal or
neonatal adverse events or any nonserious neonatal
adverse events (Table 3).
Discussion
In this randomized, double-blind trial, infants
who had prenatal exposure to buprenorphine required
significantly less morphine for the treatment
of NAS, a significantly shorter period of
NAS treatment, and a significantly shorter hospital
stay than did infants with prenatal exposure
to methadone. The superiority of buprenorphine
over methadone did not extend to differences in
the number of neonates requiring NAS treatment,
peak NAS score, head circumference, any other
neonatal outcome, or any maternal outcome.
Although buprenorphine was superior for two
of the five primary outcomes among women
who completed treatment, women who were taking
buprenorphine were more likely to discontinue
treatment. If patients with more severe
MeanTotalDoseofMorphine(mg)
14.0
12.0
8.0
10.0
6.0
4.0
2.0
0.0
Methadone
Buprenorphine
MeanDurationofNASTreatment
(days)
14.0
12.0
8.0
10.0
6.0
4.0
2.0
0.0
Methadone
Buprenorphine
MeanHospitalStay(days)
20.0
16.0
18.0
14.0
12.0
8.0
6.0
2.0
10.0
4.0
0.0
Methadone
Buprenorphine
Figure 2. Mean Neonatal Morphine Dose, Length of Neonatal Hospital Stay, and Duration of Treatment for Neonatal
Abstinence Syndrome.
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opioid dependence were more likely to leave the
buprenorphine group than the methadone group,
this factor could have accounted for better outcomes
in the buprenorphine group. However,
the absence of significant between-group differences
in baseline characteristics and in previous
and current substance-use characteristics, both
for women who completed treatment and for
Table 3. Serious and Nonserious Adverse Events Occurring during the Study.*
Adverse Event Maternal Neonatal
Methadone
(N = 89)
Buprenorphine
(N = 86)
Methadone
(N = 73)
Buprenorphine
(N = 58)
number (percent)
Serious events
Abnormal fetal health 3 (3) 0
Abnormal laboratory values 0 0 0 0
Cardiovascular symptoms 1 (1) 0 2 (3) 1 (2)
Gastrointestinal symptoms 1 (1) 1 (1) 0 1 (2)
Genitourinary symptoms 0 1 (1) 0 1 (2)
Illicit drug use 1 (1) 1 (1)
Musculoskeletal symptoms 0 0 0 1 (2)
Neurologic symptoms 0 0 0 1 (2)
Obstetrical symptoms 6 (7) 2 (2) 1 (1) 1 (2)
Postsurgical problems 0 0 0 1 (2)
Psychological problems 1 (1) 0
Psychosocial problems 1 (1) 0
Respiratory symptoms 1 (1) 0 2 (3) 0
Sexually transmitted diseases 1 (1) 0 0 0
Skin conditions 0 1 (1) 0 0
Sleep disturbances 0 1 (1)
Other 0 0 1 (1) 1 (2)
Any serious adverse event 14 (16) 8 (9) 6 (8) 1 (2)
Nonserious events
Abnormal appetite 2 (2) 0 4 (6) 1 (2)
Abnormal fetal health 6 (7) 4 (5)
Abnormal laboratory values 10 (11) 8 (9) 0 0
Blood-borne disorders 5 (6) 1 (1) 0 1 (2)
Cardiovascular symptoms 29 (33) 14 (16) 8 (11) 4 (7)
Endocrinologic symptoms 5 (6) 3 (4) 1 (1) 1 (2)
Eye, ear, nose, or throat problems 12 (14) 15 (17) 1 (1) 1 (2)
Fever 3 (3) 2 (2) 0 0
Gastrointestinal symptoms 60 (67) 47 (55) 5 (7) 4 (7)
Genitourinary symptoms 23 (26) 16 (19) 1 (1) 0
Hematopoietic or lymphatic symptoms 14 (16) 15 (17) 17 (23) 14 (24)
Illicit drug use 10 (11) 8 (9) 3 (4) 5 (9)
Dental problems 22 (25) 15 (17) 1 (1) 2 (4)
Musculoskeletal symptoms 38 (43) 28 (33) 3 (4) 1 (2)
Neuromuscular symptoms 33 (37) 29 (34) 0 0
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those who did not, suggests that differences in
the rates of treatment completion are unlikely to
explain the results. In addition, the significant
differences between groups in the amount of
morphine required for the treatment of NAS and
the duration of the hospital stay remained significant
in post hoc analyses that excluded participants
receiving 100 mg or more of methadone
daily.
Methadone has been the recommended standard
of care for opioid-dependent pregnant women,
and our double-blind study provides critical
data on the outcomes of methadone treatment.
Our findings support the safety and usefulness
of methadone treatment for opioid dependence
during pregnancy, and they also show that the
treatment of opioid-dependent pregnant women
with buprenorphine results in a clinically meaningful
reduction in the severity of NAS in their
neonates, as compared with methadone. The
mechanisms responsible for this effect remain
elusive; variability in the MDR1 genotype may
influence the transport of methadone or buprenorphine
to the fetus and thus the combination
of NAS symptoms exhibited.38,39
Our finding that there was no significant difference
between the treatment groups in rates of
opioid use during treatment is consistent with
observations in previous randomized trials involving
nonpregnant patients that methadone and
Table 3. (Continued.)
Adverse Event Maternal Neonatal
Methadone
(N = 89)
Buprenorphine
(N = 86)
Methadone
(N = 73)
Buprenorphine
(N = 58)
number (percent)
Neurologic symptoms 16 (18) 12 (14) 0 0
Obstetrical problems 29 (33) 23 (27) 3 (4) 4 (7)
Postsurgical problems 16 (18) 8 (9) 3 (4) 0
Psychological problems 24 (27) 21 (24)
Psychosocial problems 4 (5) 5 (6)

Respiratory symptoms 29 (33) 31 (36) 14 (19) 12 (21)
Sexually transmitted diseases 8 (9) 8 (9) 1 (1) 1 (2)
Skin conditions 16 (18) 12 (14) 7 (10) 2 (4)
Sleep disturbances 24 (27) 20 (23)
Somatic symptoms 19 (21) 9 (11)
Other 4 (5) 3 (4) 2 (3) 3 (5)
Any nonserious adverse event 83 (93) 66 (77) 34 (47) 29 (50)
* An alpha level of 0.05 was selected for each test of significance. Adverse events related to neonatal appetite included
weight loss, need for nutritional support, and feeding intolerance. Cardiovascular events included rapid or slow heart
rate and high or low blood pressure. Neonatal obstetrical events included asynclitic presentation and acrocyanosis.
Psychosocial events included any stressful life event (e.g., stress surrounding moving, eviction, or death of a family
member). A serious adverse event was defined as death or substantial risk of death of the mother or the infant or any
medical event that a study investigator or the data and safety monitoring board judged to be serious because it might
jeopardize the participant or might require intervention (e.g., hospitalization or extension of hospitalization). Two
women in the methadone group had multiple serious adverse events (1 had a positive serologic test for syphilis, overnight
hospitalization, and suspected premature rupture of fetal membrane; the other had lack of housing and depression),
and 12 women in this group had a single serious adverse event (2 cases each of fetal-heart-rate deceleration, premature
labor, and miscarriage and 1 case each of decreased blood flow to the fetus, pathological cardiotocographic deceleration,
heroin and cocaine overdose, gastroenteritis requiring hospitalization, amniorrhexis, and pneumonia). Two
women in the buprenorphine group had multiple serious adverse events (1 had multicystic kidney and positive drugscreening
urinalysis leading to hospitalization; the other had vaginal bleeding and preterm labor), and 6 women in this
group had a single serious adverse event (2 cases of vaginal bleeding and 1 case each of methicillin-resistant Staphylococcus
aureus, gastric hemorrhage, hospitalization for removal of vaginal condyloma, and false labor). One neonate in
the methadone group had multiple serious adverse events (2 surgeries for dextrocardia), and 4 neonates in this group
had a single serious adverse event (1 case each of premature delivery [after which the neonate died], suspected apnea,
respiratory distress, and cyanosis). One neonate in the buprenorphine group had all 8 serious adverse events listed in
the table (e.g., multiple surgeries, renal failure, and hypoxic ischemic encephalopathy) and subsequently died.
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buprenorphine cause similar reductions in illicit
opioid use.32 Moreover, the low levels of concomitant
use of alcohol and illicit drugs, in combination
with the nonsignificant differences in
other maternal outcomes between the methadone
and buprenorphine groups, suggest that these
two medications, in the context of comprehensive
care, do not differ markedly in terms of their
effect on maternal treatment outcomes at delivery.
Thus, the less severe NAS in neonates exposed
to buprenorphine as compared with those
exposed to methadone cannot be attributed to
different effects of these agents on the outcomes
of maternal opioid treatment.
These results must be considered in light of
the markedly different rates of attrition, which
were largely due to greater patient dissatisfaction
with buprenorphine than with methadone. Although
this finding is similar to the results of
trials in nonpregnant patients receiving doses
within similar acceptable therapeutic ranges,12
the reasons for the difference in attrition rates
are unknown. It is possible that withdrawal was
inadequate before the first dose of buprenorphine
was administered or that buprenorphine
induction was too slow.40,41 In both cases, administering
the initial induction dose in smaller increments
throughout the day might reduce the
dropout rate.42 It is also possible that there is
individual variation in the absorption of sublingual
buprenorphine tablets. Another possible explanation
is that an abrupt cessation of treatment
may be more comfortable for patients taking buprenorphine
than for those taking methadone
because of the milder effects of withdrawal with
buprenorphine.43 Buprenorphine may have less
potent agonistic effects than methadone in mitigating
craving and other symptoms of withdrawal,
especially in patients who are highly
dependent on opioids. Whatever the reasons, the
fact that two primary outcomes remained significant
in post hoc analyses omitting participants
whose methadone dose at delivery exceeded
100 mg lends support to our general conclusions,
particularly given the lost power associated with
removing 19% of our sample (25 of 131 participants).
The greater rate of satisfaction with methadone
affirms the important role it plays in treating
pregnant women who are dependent on
opioids. Moreover, given the partial agonistic
activity of buprenorphine and its ceiling effect at
maximal doses, it will not be the optimal treatment
for all pregnant patients with a dependency
on opioids. Further research is needed to
assess the effectiveness of methods intended to
reduce buprenorphine-specific attrition and to examine
factors that may predict maternal and neonatal
responses to each medication (e.g., pharmacogenomics44),
making it feasible to identify
subpopulations of pregnant patients who are
more likely to have a response to one medication
than to the other.
In summary, our findings are consistent with
the use of buprenorphine as an alternative to
methadone for the treatment of opioid dependency
during pregnancy. Although there were no
significant differences in overall rates of NAS
among infants exposed to buprenorphine and
those exposed to methadone, the benefits of
buprenorphine in reducing the severity of NAS
among neonates with this complication suggest
that it should be considered a first-line treatment
option in pregnancy. In selecting a course of
treatment, however, clinicians should take into
account the possibility of reduced adherence and
the ceiling effect of this medication as compared
with methadone.
Supported by grants from the National Institute on Drug
Abuse (R01 DA015778, to Brown University; R01 DA015764, to
Johns Hopkins University; R01 DA018417, to the Medical University
of Vienna; R01DA015738, to Thomas Jefferson University;
R01 DA015741, to the University of Toronto; R01 DA 018410 and
M01 RR109, to the University of Vermont; R01 DA 017513 and
M01 RR00095, to Vanderbilt University; and R01DA15832, to
Wayne State University).
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank the patients for their participation in this study; the
coinvestigators, clinical and research staff, and members of the
Data and Safety Monitoring Board for their effort and dedication
to this study; and Reckitt Benckiser Healthcare, Hull, United
Kingdom, for providing the buprenorphine and placebo product
through the NIDA.
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